Cracking a Cold Case
A 30-year-old medical puzzle leads researchers to develop a new molecular therapy
Roisin McGuigan |
Steven Francis, a patient at McGill University Health Centre, was at the center of a mystery. From an early age he had experienced fungal infections, an inflamed colon, shingles, respiratory problems, impeded growth, and a host of other problems. But no one could explain why.
At 33, he was referred to Donald Vinh, who went searching for answers. “When this patient was referred to me, I went over his entire file in detail, covering some 30 years and literally filling two large cardboard boxes. I also looked at his family history. Since the 1980s, many new immune deficiencies have been identified, and I was able to apply the knowledge from these advances to solve the case,” he says.
And solve it he did – discovering that Steven had a mutation in ZAP-70. The ZAP70 protein helps to activate T cells and is critical for immune system function – and usually, mutations of the gene require a hematopoietic stem cell transplant for the patient to survive beyond early childhood. “Leaky” deficiencies in the gene are less common, with only a few cases reported in the literature. As stem cell transplants could prove risky for older patients, Vinh and his colleagues looked at a different approach: mutation-targeted molecular therapy.
Steven’s specific mutation affects the splicing of ZAP-70, so the team designed an antisense morpholino oligonucleotide that targets the splice site generated by the mutation. This allowed the protein to be successfully synthesized ex vivo. If the treatment can be translated to humans, it could potentially improve immune system function.
Vinh is hopeful that the discovery of ZAP-70 mutations in adults, and the proof-of-concept study of a potential treatment, could lead to great advances in the field. “There are definitely more steps to take before we can test this treatment. For one thing, we have to convince the industry to support us. When Steven can finally get the benefit of the treatment, I'll be able to count this as a victory,” he adds.
- C Gavino et al., “Morpholino-based correction of hypomorphic ZAP70 mutation in an adult with combined immunodeficiency” J Allergy Clin Immunol, 139, 1688–1692 (2017). PMID: 28216435.